A paramagnetic chemical exchange-based MRI probe metabolized by cathepsin D: design, synthesis and cellular uptake studies.

Overexpression of the aspartyl protease cathepsin D is associated with certain cancers and Alzheimer's disease; thus, it is a potentially useful imaging biomarker for disease. A dual fluorescence/MRI probe for the potential detection of localized cathepsin D activity has been synthesized. The probe design includes both MRI and optical reporter groups connected to a cell penetrating peptide by a cathepsin D cleavable sequence. This design results in the selective intracellular deposition (determined fluorimetrically) of the MRI and optical reporter groups in the presence of overexpressed cathepsin D. The probe also provided clearly detectable in vitro MRI contrast by the mechanism of paramagnetic chemical exchange effects (OPARACHEE).

[1]  M. Pagel,et al.  An amine-derivatized, DOTA-loaded polymeric support for Fmoc Solid Phase Peptide Synthesis. , 2009, Tetrahedron letters.

[2]  A. Spek,et al.  Synthesis of conformationally constrained peptidomimetics using multicomponent reactions. , 2009, The Journal of organic chemistry.

[3]  M. Suchý,et al.  Synthetic Strategies Toward N‐Functionalized Cyclens , 2008 .

[4]  Martin Fusek,et al.  Cathepsin D--many functions of one aspartic protease. , 2008, Critical reviews in oncology/hematology.

[5]  R. Bartha,et al.  A new synthesis of cystamine modified Eu3+ DOTAM-Gly-Phe-OH: a conjugation ready temperature sensitive MRI contrast agent. , 2008, Organic & biomolecular chemistry.

[6]  A Dean Sherry,et al.  Chemical exchange saturation transfer contrast agents for magnetic resonance imaging. , 2008, Annual review of biomedical engineering.

[7]  S. Kelley,et al.  Cell-penetrating peptides as delivery vehicles for biology and medicine. , 2008, Organic & biomolecular chemistry.

[8]  R. Bartha,et al.  Analogs of Eu3+ DOTAM-Gly-Phe-OH and Tm3+ DOTAM-Gly-Lys-OH: synthesis and magnetic properties of potential PARACEST MRI contrast agents. , 2008, Bioorganic & medicinal chemistry.

[9]  P. Durand,et al.  Detection of enzymatic activity by PARACEST MRI: a general approach to target a large variety of enzymes. , 2008, Angewandte Chemie.

[10]  P. Lewczuk,et al.  Neurochemical dementia diagnostics: State of the art and research perspectives , 2008, Proteomics.

[11]  Craig K. Jones,et al.  A sensitive PARACEST contrast agent for temperature MRI: Eu3+‐DOTAM‐glycine (Gly)‐phenylalanine (Phe) , 2008, Magnetic resonance in medicine.

[12]  Luis M. De Leon-Rodriguez,et al.  The synthesis and chelation chemistry of DOTA-peptide conjugates. , 2008, Bioconjugate chemistry.

[13]  R. Lenkinski,et al.  MRI detection of paramagnetic chemical exchange effects in mice kidneys in vivo , 2007, Magnetic resonance in medicine.

[14]  R. Bartha,et al.  A robust and convergent synthesis of dipeptide-DOTAM conjugates as chelators for lanthanide ions: new PARACEST MRI agents. , 2007, Bioconjugate chemistry.

[15]  M. Pagel,et al.  Enzyme-responsive PARACEST MRI contrast agents: a new biomedical imaging approach for studies of the proteasome. , 2007, Contrast Media & Molecular Imaging.

[16]  Byunghee Yoo,et al.  A PARACEST MRI contrast agent to detect enzyme activity. , 2006, Journal of the American Chemical Society.

[17]  G. Cravotto,et al.  How to determine free Gd and free ligand in solution of Gd chelates. A technical note. , 2006, Contrast media & molecular imaging.

[18]  V. Laurent-Matha,et al.  Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis. , 2006, Cancer letters.

[19]  A Dean Sherry,et al.  Paramagnetic lanthanide complexes as PARACEST agents for medical imaging. , 2006, Chemical Society reviews.

[20]  Robert E Lenkinski,et al.  On-resonance low B1 pulses for imaging of the effects of PARACEST agents. , 2005, Journal of magnetic resonance.

[21]  H. Rochefort.  Cathepsin D in breast cancer , 1990, Breast Cancer Research and Treatment.

[22]  Roger Y Tsien,et al.  Tumor imaging by means of proteolytic activation of cell-penetrating peptides. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[23]  M. Schindl,et al.  Cathepsin D in ovarian cancer: prognostic value and correlation with p53 expression and microvessel density. , 2004, Gynecologic oncology.

[24]  Marcel Garcia,et al.  Cathepsin D: A protease involved in breast cancer metastasis , 1990, Cancer and Metastasis Reviews.

[25]  N. Gebbia,et al.  Cathepsin D expression levels in nongynecological solid tumors: Clinical and therapeutic implications , 2004, Clinical & Experimental Metastasis.

[26]  Robert E Lenkinski,et al.  PARACEST agents: modulating MRI contrast via water proton exchange. , 2003, Accounts of chemical research.

[27]  C. Kushmerick,et al.  Changes in Ca2+ channel expression upon differentiation of SN56 cholinergic cells , 2001, Brain Research.

[28]  H. Tazaki,et al.  Role of cathepsin D in prostatic cancer cell growth and its regulation by brefeldin A , 2001, World Journal of Urology.

[29]  R S Balaban,et al.  A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST). , 2000, Journal of magnetic resonance.

[30]  A. R. Massensini,et al.  Expression of the Vesicular Acetylcholine Transporter, Proteins Involved in Exocytosis, and Functional Calcium Signaling in Varicosities and Soma of a Murine Septal Cell Line , 1999, Journal of neurochemistry.

[31]  A. Akamine,et al.  Characterization of new fluorogenic substrates for the rapid and sensitive assay of cathepsin E and cathepsin D. , 1999, Journal of biochemistry.

[32]  M. Goedert,et al.  Cathepsin D displays in vitro β-secretase-like specificity , 1997, Brain Research.

[33]  C. Tarnus,et al.  Processing of β-Amyloid Precursor Protein by Cathepsin D* , 1996, The Journal of Biological Chemistry.

[34]  Gary T. Wang,et al.  Cathepsin D from Alzheimer's-Diseased and Normal Brains , 1995, Experimental Neurology.

[35]  Jinhe Li,et al.  Gene expression and cellular content of cathepsin D in Alzheimer's disease brain: Evidence for early up-regulation of the endosomal-lysosomal system , 1995, Neuron.

[36]  J. Vonsattel,et al.  Elevated Levels of the Endosomal‐Lysosomal Proteinase Cathepsin D in Cerebrospinal Fluid in Alzheimer Disease , 1995, Journal of neurochemistry.

[37]  B. Wainer,et al.  Acetylcholine synthesis and release is enhanced by dibutyryl cyclic AMP in a neuronal cell line derived from mouse septum , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[38]  R. Nixon,et al.  Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[39]  B. Wainer,et al.  Development and characterization of clonal cell lines derived from septal cholinergic neurons , 1990, Brain Research.

[40]  J. Tang,et al.  Mode of inhibition of acid proteases by pepstatin. , 1976, The Journal of biological chemistry.